Field of the Invention
The present invention relates to improvement of mammalian, including human, biological conditions impacted by, or mediated by, galectin-3. Galectin-3 is a member of the lectin family, of which at least fourteen (14) mammalian galectins have been identified. Galectin-3 is approximately 30 kDa and, like all galectins, contains a carbohydrate-recognition-binding domain (CRD) of about one hundred thirty (130) amino acids that enable the specific binding of β-galactosides. Galectin-3 is encoded by a single gene, LGALS3, located on chromosome 14, locus q21-q22. It is expressed in the nucleus, cytoplasm, mitochondrion, cell surface, and extracellular space, and can circulate in the blood stream. This protein has been shown to be involved in a large number of biological processes, including cell adhesion, cell migration, cell invasion, cell activation and chemoattraction, cell growth and differentiation, cell cycle, and apoptosis. Given galectin-3's broad biological functionality, it has been demonstrated to be involved in a large number of disease states or medical implications. Studies have also shown that the expression of galectin-3 is implicated in a variety of processes associated with heart failure, including myofibroblast proliferation, fibrogenesis, tissue repair, inflammation, and ventricular and tissue remodeling. Elevated levels of galectin-3 in the blood have been found to be significantly associated with higher risk of death in both acute decompensated heart failure and chronic heart failure populations, as well as constituting a biomarker of cancer progression to a metastatic stage.
Background of the Invention
In 2006, U.S. patent application Ser. No. 11/485,955 was filed, a utility patent application claiming priority from a 2005 provisional application. This patent application, making reference to earlier disclosures of administration of modified alginates and pectins, such as those in U.S. Pat. Nos. 6,274,566 and 6,462,029, disclosed for the first time the utility of using very specific low molecular weight pectins, such as PectaSol-C MCP available from EcoNugenics of Santa Rosa, Calif. This modified citrus pectin (MCP) and similar very low molecular weight pectins (molecular weight of 20,000 Daltons or less, preferably about 10,000 Daltons) is shown in U.S. patent application Ser. No. 11/485,955 to be effective in stimulating a variety of immune responses in mammals.
In the years since the filing which first set forth the administration of these low molecular weight modified citrus pectins, and similar pectins, research has demonstrated that at least one mode of action of MCP is the binding of galectin-3 molecules. This binding, an inherent feature of the inventions disclosed in U.S. patent application Ser. No. 11/485,955, is also a central mode of action in the later-filed U.S. patent application Ser. No. 12/984,843, filed Jan. 5, 2011 directed to the inhibition of certain cancers. In fact, it is now clear that administering PectaSol-C MCP or other low molecular weight pectins at the dosage levels of 5-1,500 mg/kg of body weight per day, a preferred range of 10 mg/kg/day to 1,000 mg/kg/day inherently binds galectin-3 molecules in mammals in need of same in a variety of biological systems, providing therapeutic benefit against many of the disease conditions mentioned.
Thus, the activity of galectin-3 in aggravating or promoting cancer, as well as the ability of a cancer to metastasize, is widely commented on in the literature following the 2006 disclosure of the effectiveness of low molecular weight pectins like PectaSol-C in promoting immune systems. These literature findings stress repeatedly the importance of binding or reducing the circulating concentration or titer of galectin-3, and/or inactivating glaectin-3 through galectin-3 binders such as PectaSol-C. See, for example, Wang et al, Cell Death and Disease, 1-10 (2010) (galectin-3 inhibition promotes treatment) and Yu et al, J. Biol. Chemistry, Vol. 282, 1, pp. 773-781 (2007) establishing that galectin-3 interactions may enhance formation of cancer or transformation of metastatic cancer.
Similar reports link acceleration of cancer formation and transformation to circulating galectin-3 concentrations, and suggest that reducing galectin-3 circulating concentrations, reducing its free expression or otherwise reducing available galectin-3 or galectin-3 interactions improve cancer prognosis. Zhao et al, Cancer Res. 69, 6799-6806 (2009), Zhao et al, Molecular Cancer 9, 154, 1-12 (2010) and Wang et al, Am. J. of Pathology, 174, 4, 1515-1523 (2009) wherein siRNA-induced reduction of galectin-3 is shown to slow the course of prostate cancer. Clearly, there is substantial literature that supports the conclusion that reducing circulating galectin-3, either by blocking its expression, or by binding it, as inherently disclosed in the 2006 filing of U.S. patent application Ser. No. 11/485,955, is important in controlling cancer.
Circulating galectin-3 is implicated in a wide variety of biological conditions, however. Cardiac fibrosis is gaining significant attention as a complicating risk factor in cardiac disease, and in particular, chronic heart failure (CHF). Lok et al, Clin. Res. Cardiol, 99, 323-328 (2010). DeFillipi et al, U.S. Cardiology, 7,1, 3-6 (2010) clearly indicate that circulating galectin-3 is an important factor in fibrosis of many organs and organ systems, and that reducing circulating galectin-3 may have an important role in remediating cardiac injury and progression to heart failure (HF). Similarly, Psarras et al, Eur. Heart J., Apr. 26, 2011 demonstrate that reduction in galectin-3 levels in the myocardium may reduce fibrosis in the heart and improve outlook. De Boer et al, Ann. Med., 43,1, 60-68 (2011) identify galectin-3 as a key indicator in cardiac health. Shash et al, Eur J. Heart Fail., 12,8, 826-32 (2011) identify galectin-3 levels as a key agent in heart failure through fibrosis. De Boer et al. Eur. J. Heart Fail., 11, 9, 811-817 (2009) link an increase in galectin-3 expression and presence to heightened fibrosis, and heart failure. The same article links galectin-3 to inflammation. Inflammation is the hallmark of arteriosclerosis and therefore galectin-3 levels also contribute to coronary artery disease, peripheral artery disease, strokes, and vascular dementia.
Fibrosis and inflammation, both mediated to some degree by galectin-3 (cellular or circulating) are implicated in a variety of conditions of the mammalian body, not just cardiac injury and heart failure. The binding of galectin-3 achieved by administration of low molecular weight pectins (at least, as reflected in U.S. patent application Ser. No. 11/485,955 10,000-20,000 Daltons molecular weight such as PectaSol MCP) is effective in reducing trauma due to kidney injury. Kolatsi-Jannou et al, PlusOne, 6, 4, e18683 (2011). The reduction in circulating galectin-3 levels is also indicated to reduce inflammation associated with type 2 diabetics, and similar metabolic diseases. Weigert et al, J. Endocrinol. Metab. 95, 3,1404-1411(2010). Thus, high levels of galectin-3 have been linked to thyroid cancer, Sethi et al, J. Exp. Ther. Oncol., 8, 4,341-52 (2010) and reduction of galectin-3 expression and circulation may delay or reduce tumor cell transformation. Chiu et al, Am J. Pathol. 176, 5, 2067-81 (2010).
As noted, galectin-3 is implicated in a wide variety of biological conditions, and a reduction in galectin-3 activity, such as that which can be achieved by galectin-3 binding with PectaSol-C MCP and similar low molecular weight pectins may be of value in treating gastric ulcerative conditions. Srikanta, Biochimie, 92, 2, 194-203 (2010). Kim et al, Gastroenterology, 138, 1035-45 (2010) indicate that reducing galectin-3 levels may be of therapeutic value in reducing gastric cancer progression. By the same methodology, reducing galectin-3 levels sensitizes gastric cancer cells to conventional chemotherapeutic agents. Cheong et al, Cancer Sci., 101, 1, 94-102 (2010). Galectin-3 is implicated in a wide variety of gastrointestinal conditions. Reducing galectin-3, by binding for example, may reduce inflammation in the gut mucosa, making MCP an important agent for treatment of ulcerative colitis, non-specific colitis and ileitis, Crohn's disease, Celiac disease, and gluten sensitivity. Fowler et al, Cell Microbiol., 81,1,44-54 (2006).
Biliary artesia, a liver disease, is associated with extensive fibrosis of the liver linked with elevated galectin-3 levels. Honsawek et al, Eur. J. Pediatr. Surg., Apr. 2011. Reduction of galectin-3 levels resulted in a general improvement in hepatic health, including reducing inflammation, hepatocyte injury and fibrosis. Federici et al, J. Heptal., 54, 5, 975-83 (2011). See also, Liu et al, World J. Gastroenterol. 14,48, 7386-91 (2008) which reported, following Applicant's teaching in 2005 and 2006 to administer low molecular weight MCP, that MCP inhibited liver metastases of colon cancer and reduced galectin-3 concentrations. MCP may be used for prevention of liver inflammation, liver fibrosis and liver cirrhosis as well as post-disease liver damage, including the various viral hepatitis disease (B, C, and others) and may be used as well in the treatment of parasitic and chemical hepatitis, chemical liver damage, and others.